Conditioned Open-label Placebos to Facilitate Opioid Reduction in Patients With Chronic Non-cancer Pain (ROM)

Conditioned Open-label Placebos to Facilitate the Reduction of Opioid Medication (ROM) in Patients With Chronic Non-cancer Pain: a Randomized Controlled Trial

This study aims to evaluate whether the reduction of the daily morphine equivalent dose (MED) in patients with chronic non-cancer pain (CNCP) can be decreased with an open-label placebo (OLP) intervention in comparison to an electronic monitoring (EM) control group. The participants will receive the intervention (OPL or EM) over the duration of six weeks. Diverse psychological and health measures will be assessed with questionnaires over the course of the intervention. Furthermore, evaluation outcomes, qualitative outcomes and safety outcomes will be assessed. It is hypothesized that the OLP-intervention group in comparison to the EM-control group will have a significantly lower consumption of MED over the course of the study. Furthermore, this study aims to evaluate whether the OLP intervention can reduce opioid withdrawal symptoms in comparison to the control group.

Study Overview

• Status: Recruiting
• Conditions: Chronic Non-cancer Pain
• Intervention / Treatment: Other: P-Dragees blue Lichtenstein, Placebo dragees; Other: Control group (EM)

Detailed Description

CNCP is a major global health problem and is often treated with opiod medication, although risks outweigh the benefits. Therefore, recent studies suggest that an open-label placebo (OLP) treatment, the placebo treatment with full disclosure of being a placebo, has proven to be an effective, clinically relevant, and evidence-based treatment in CNCP syndromes. Furthermore, a new line of research indicated that OLPs have been shown to be feasible for the reduction of active medication in opioid use disorder. In line with the conditioning paradigm, the drug as the unconditioned stimulus is paired with the neutral stimulus of an OLP in a learning phase. Then, the OLP alone becomes a conditioned stimulus.

• Study Type: Interventional
• Enrollment (Estimated): 86
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Cosima Locher, PhD; Phone Number: +41 44 255 12 03; Email: Cosima.Locher@usz.ch
• Study Contact Backup: Name: Kiara Bodonyi, MSc; Phone Number: +41 44 255 14 24; Email: Kiara.Bodonyi@usz.ch

Study Locations

• Switzerland
  • Zurich, Switzerland, 8006
    • Recruiting
    • University Hospital Zurich, Department of Consultation-Liaison Psychiatry and Psychosomatic Medicine
    • Contact: Cosima Locher, PhD; Phone Number: +41 44 255 12 03; Email: cosima.locher@ubas.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Signed Informed Consent
• ≥ 18 years of age
• German speaking
• Chronic non-cancer pain ≥ 6 months in duration
• Chronic opioid medication for > 3 months
• Oral intake of opioid medication
• Motivation for opioid reduction
• Participants have a primary treating physician who performs the reduction of the opioid medication
• Having access to a computer or tablet with an email-account

Exclusion Criteria:

• Having psychotic symptoms
• Suicidality
• Cognitive impairment to everyday life
• Planned surgery within the next two months
• Known illegal drug or harmful alcohol consumption
• Intolerance of the ingredients of the placebo pill (e.g., lactose, sucrose, corn-starch)
• Serious health problems that make study participation impossible
• Simultaneous participation in other studies with investigational drugs or CNCP specific interventions

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Open-Label Placebo; The intervention involves administering "P-Dragees blue Lichtenstein," blue placebo pills devoid of active ingredients. Each pill contains lactose monohydrate; magnesium stearate (Ph. Eur.); microcrystalline cellulose; sucrose; glucose syrup; corn-starch; highly dispersed silicon dioxide; white clay; macrogol glycerol hydroxy stearate (Ph. Eur.); Gum arabic; montanglycol wax; povidone (K 25); talcum; titanium dioxide (E 171); calcium carbonate; macrogol 6000; patent blue V; aluminium salt (E 131). Participants will be informed that the pills are placebos and will be instructed to pair them with opioid medication for 7 days. After 7 days until the end of the study they will be instructed to continue to pair their opioid medication with an OLP pill and take additionally placebo pills on the basis of their need. An evidence-based rationale will be provided, explaining why the placebo treatment is deemed effective for pain. This rationale will precede the OLP intake procedure.	Other: P-Dragees blue Lichtenstein, Placebo dragees; In the intervention group, open-label placebos are administered within the framework of a mind-body management intervention approach, which in turn is consistent with the biopsychosocial model of pain and with a patient-centred approach. The verbal interaction follows the four discussion points: Opioids work by telling the body that participants are not experiencing as much pain;; Placebos should be taken every time an opioid is taken which supports the reduction of opioid medication (shown by previous studies);; By pairing the pills together the brain will learn to release chemicals like endorphins that cause pain-relief in response to the placebo, just as it does in response to the opioid;; At a certain point, placebos might provide adequate pain relief, and the participants might need less opioids.
Other: Electronic monitoring (EM) control group; EM is a method to objectively measure adherence and serves as the primary intervention component on the basis of which adherence trajectories will be discussed. The participants in the EM control group will receive an evidence-based rational designed to foster positive expectations and will be instructed on the mechanisms of EM. The EM control group is structurally equivalent to the OLP group referring to the number and duration of contacts between participants and the study team members as well as to the format of the intervention and the quality of the interaction.	Other: Control group (EM); In the EM control group, the focus lies on the electronic monitoring (EM) of the opioid intake. The treatment rationale is designed to facilitate the reduction of opioid medication by promoting a positive attitude towards the implementation of the reduction. The verbal interaction follows the four discussion points: The collection of EM data allows for greater patients' sense of agency over medication treatment;; Tracking of opioid medication use supports the reduction of opioid medication (shown by previous studies);; The EM is a useful tool, and daily recording of opioid medication intake should be done;; At a certain point, EM might provide adequate pain relief, and participants might need less opioids.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Daily opioid consumption (MED):	Cumulative dose (i.e. total amount) of opioid pain medication consumption based on daily morphine equivalent doses (MED). Data is collected in SEMA3 app.	Daily measure: starts on day 1 after the first intervention visit (baseline, day 0) after randomization and ends on day 42 at the end of the study.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Subjective opioid withdrawal symptoms	Subjective opioid withdrawal will be assessed with the Subjective Opiate Withdrawal Scale (SOWS). The intensity of the withdrawal symptoms is rated by the patient on a scale between 0 (= not at all) and 4 (= extremely), the scores for individual symptoms are added to a total sum score, which can range from 0 to 64. The secondary endpoint will be the subjective opioid withdrawal score at study end (t3).	Measured three times: on day 0 at the first intervention visit (baseline), on day 7, and on day 42 at the end of the study.
Pain severity	Pain severity is assessed using the ICD-11 specifiers or 'extension codes'. The index combines patient-assessed ratings of pain intensity, pain-related distress and pain-related interference. Each of these ratings is assessed on an 11-point NRS rating scale, and these are mapped into the following categories depending on the NRS score: none = NRS 0, mild = NRS 1 - 3, moderate = NRS 4 - 6 and severe = NRS 7 - 10.	Measured three times: on day 0 at the first intervention visit (baseline), on day 7, and at the end of the study on day 42.
Pain disability	Pain disability is assessed using the pain disability index (PDI) to determine the subjective degree of self-reported impairment caused by the pain problem in everyday life. Seven domains of life are assessed: (1) family and domestic responsibilities, (2) recreation, (3) social activities, (4) occupation, (5) sexual life, (6) self-care and (7) essential activities. The scale ranges from 0 "no impairment" (minimum) - 10 "full impairment" (maximum).	Measured three times: on day 0 at the first intervention visit (baseline), on day 7, and at the end of the study on day 42.
Anxiety	Anxiety is assessed using the German version of the GAD-7. It is a brief instrument for assessing self-reported generalized anxiety disorder (GAD) symptoms with seven items asking about the main diagnostic criteria of GAD according to the DSM-IV and the ICD-10 criteria. The questions refer to the past two weeks. The scale ranges from "not at all" (minimum); "On some days"; "On more than half of the days"; "almost every day" (maximum).	Measured three times: on day 0 at the first intervention visit (baseline), on day 7, and at the end of the study on day 42.
Depression	Depression is assessed using Patient Health Questionnaire (PHQ-D) consisting of nine items referring to the past two weeks. The German version of the PHQ was derived from the 'Prime MD Patient Health Questionnaire' and is based on the criteria of the DSM-IV. The scale ranges from "not at all" (minimum); "On some days"; "On more than half of the days"; "almost every day" (maximum).	Measured three times: on day 0 at the first intervention visit (baseline), on day 7, and at the end of the study on day 42.
Pain Opioid Analgesics Beliefs Scale - Cancer	The POABS-CA in the German version measures pain opioid beliefs based on two components with 10 items and a 5-point Likert scale ranging from 0 ("strongly disagree") to 4 ("strongly agree"). The higher the score, the more negative was the opinion about the use of opioid analgesics for cancer pain, and the stronger was the belief that pain should be endured.	Measured three times: on day 0 at the first intervention visit (baseline), on day 7, and at the end of the study on day 42.
Treatment Expectancy 1	Expectation measures will be measured in analogy to the most relevant outcomes. First, subjectively expected amount (dose) of opioid medication taken will be examined. For this, the following item will be used at the end of the study "How much opioid medication do you think you will be taking at the end of the study?" The item is answered by naming the type of medication, frequency and amount (dose) of medication.	One-time assessment: measured on day 0 at the first intervention visit (baseline).
Treatment Expectancy 2	Expectation measures will be measured in analogy to the most relevant outcomes. Second, to measure the expected withdrawal symptoms at the end of the study, items from the SOWS questionnaire will be used, which are expanded with instructions regarding the expectation.	One-time assessment: measured on day 0 at the first intervention visit (baseline).
Placebo pill count	The intake of placebo pills by the OLP-group will be electronically monitored using survey provided by the app SEMA3. For statistical analysis a ratio will be calculated. A value of the ration close to 1 indicated a more accurate data entry of the placebo pill intake.	Daily measure: starts 1 day after the first intervention visit (baseline, day 0) after randomization and ends on day 42 at the end of the study.
Opioid adherence	Opioid adherence trajectories will be measured with the app SEMA3 in both groups. In the EM control group, a print of the actual data report from the app (i.e. graph reflecting the pattern of opioid medication intake) will be the basis for the EM-Feedback.	Daily measure: starts 1 day after the first intervention visit (baseline, day 0) after randomization and ends on day 42 at the end of the study.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rationale credibility	The rationale credibility of the OLP intervention will be assessed in the OLP group at study end. The following questions will be assessed: "How credible did you find the explanation of why placebo treatment can work?", "During the study, did you believe that these were placebo tablets that did not contain a pharmacologic agent?", "Did you find the explanation of why the placebo intervention may work helpful?", "How helpful did you find the explanation of why placebo treatment can work?". Answers will be rated on a Likert scale ranging from 0 = Not at all to 4 = Extremely.	One-time assessment: measured on day 42 at the end of the study.
Placebo understanding	The understanding of placebo will be assessed in both study groups (OLP and control group) at study end using a questionnaire which assesses responders' attitudes regarding non-specific therapies. The first three items of this questionnaire specifically assess the placebo understanding and will be used for this study. The scales differ for the different items. Scale question 1: "I have never heard of the term"; "I have heard the term before, but I do not know"; "A placebo is ... (open question)" Scale question 2: "For me the term is rather positive" "For me the term is neutral, neither positive nor negative"; "For me the term is rather negative"; "I do not know" Scale question 3. "Yes, very often"; "Yes, but rarely"; "No"; "I do not know" Additionally participants are asked, if their understanding of placebos might have changed across the study. Scale: "Yes, to the positive because ... (open question)"; Yes, to the negative because ... (open question)"; "No"; "I do not know"	One-time assessment: measured on day 42 at the end of the study.
Patient Provider Connection	The Patient Provider Connection is a subscale of the German version of the Healing Encounters and Attitudes List (HEAL) which can be used independently from the six subscales. The seven items are rated on a five-point Likert scale ranging from "not at all" to "very strong" assessing participants' attitudes towards patient-provider connection as a non-specific treatment effect. The scale ranges from 0 "not at all" (minimum) to "very much" 4 (maximum)	One-time assessment: measured on day 42 at the end of the study.
Medication history	Participants' non-opioid medication intake will be assessed by asking the participants about the medication's name, dosage, and reason for intake. Participants will also be asked about the date of prescription.	Measured two times: on day 0 at the first intervention visit (baseline) and on day 42 at the end of the study.
Primary treating physicians' acceptability of the OLP approach:	Before the start of the study the primary treating physicians will be asked about their acceptability of the OLP approach from patient and physicians point of view. All items will be rated on a five- or seven-point Likert scale.	One-time assessment, measured before study start: on day -14, prior to the first intervention visit (baseline, day 0).
Primary treating physicians' treatment expectancies	The primary treating physicians will be given the same questionnaire on treatment expectations as the participants. They will be asked about their subjective expectation of their patients' use of opioid medication and their subjective expectation of their patients' withdrawal symptoms at the end of the study. In addition, the primary treating physicians will be asked to assess their patients' motivation to reduce opioid pain medication. Motivation will be assessed with the following questions on a satisfaction ruler ranging from 0 % to 100 %: 1. "How satisfied is your patient currently with his opioid medication?", 2. "How confident are you that your patient can change her/his use of opioid medication?".	One-time assessment, measured before study start: on day -14, prior to the first intervention visit (baseline, day 0).
Qualitative Outcomes	The qualitive outcomes will be assessed with an audio recorded semi-structured interviews and will consist of general questions about placebos and core question about the experience of the OLP intervention, acceptability of the OLP approach and prerequisites, ideas and concerns regarding practical OLP implementation.	One-time assessment: measured at the end of the study on day 42.
Additional Symptoms	Participants answer three questions regarding additional symptoms that might have occurred since the last visit at the study site. The questions are the following: "How have you been since the last visit?" (open answer format); "Did you have certain symptoms?" (yes/no); If the participant answered yes in question 2, a follow up question will be displayed: "Please describe the symptoms you had in detail." (open answer format)	Measured two times: on day 7 after the first intervention visit (baseline) and on day 42.

Collaborators and Investigators

• Sponsor: Cosima Locher
• Collaborators: Brown University; University of Basel
• Investigators: Principal Investigator: Cosima Locher, PhD, USZ

Publications and helpful links

General Publications

• Morales-Quezada L, Mesia-Toledo I, Estudillo-Guerra A, O'Connor KC, Schneider JC, Sohn DJ, Crandell DM, Kaptchuk T, Zafonte R. Conditioning open-label placebo: a pilot pharmacobehavioral approach for opioid dose reduction and pain control. Pain Rep. 2020 Jul 20;5(4):e828. doi: 10.1097/PR9.0000000000000828. eCollection 2020 Jul-Aug.
• Buergler S, Sezer D, Gaab J, Locher C. The roles of expectation, comparator, administration route, and population in open-label placebo effects: a network meta-analysis. Sci Rep. 2023 Jul 22;13(1):11827. doi: 10.1038/s41598-023-39123-4.
• Belcher AM, Cole TO, Massey E, Billing AS, Wagner M, Wooten W, Epstein DH, Hoag SW, Wickwire EM, Greenblatt AD, Colloca L, Rotrosen J, Magder L, Weintraub E, Wish ED, Kaptchuk TJ. Effectiveness of Conditioned Open-label Placebo With Methadone in Treatment of Opioid Use Disorder: A Randomized Clinical Trial. JAMA Netw Open. 2023 Apr 3;6(4):e237099. doi: 10.1001/jamanetworkopen.2023.7099.
• Bernstein MH, Magill M, Weiss AP, Kaptchuk TJ, Blease C, Kirsch I, Rich JD, Becker SJ, Mach S, Beaudoin FL. Are Conditioned Open Placebos Feasible as an Adjunctive Treatment to Opioids? Results from a Single-Group Dose-Extender Pilot Study with Acute Pain Patients. Psychother Psychosom. 2019;88(6):380-382. doi: 10.1159/000503038. Epub 2019 Sep 27. No abstract available.
• Estudillo-Guerra MA, Mesia-Toledo I, Schneider JC, Morales-Quezada L. The Use of Conditioning Open-Label Placebo in Opioid Dose Reduction: A Case Report and Literature Review. Front Pain Res (Lausanne). 2021 Jul 12;2:697475. doi: 10.3389/fpain.2021.697475. eCollection 2021.
• Flowers KM, Patton ME, Hruschak VJ, Fields KG, Schwartz E, Zeballos J, Kang JD, Edwards RR, Kaptchuk TJ, Schreiber KL. Conditioned open-label placebo for opioid reduction after spine surgery: a randomized controlled trial. Pain. 2021 Jun 1;162(6):1828-1839. doi: 10.1097/j.pain.0000000000002185.
• Sezer D, de Leeuw M, Netzer C, Dieterle M, Meyer A, Buergler S, Locher C, Ruppen W, Gaab J, Schneider T. Open-Label Placebo Treatment for Acute Postoperative Pain (OLP-POP Study): Study Protocol of a Randomized Controlled Trial. Front Med (Lausanne). 2021 Nov 5;8:687398. doi: 10.3389/fmed.2021.687398. eCollection 2021.

Study record dates

Study Major Dates

• Study Start (Actual): June 12, 2024
• Primary Completion (Estimated): May 1, 2026
• Study Completion (Estimated): July 1, 2026

Study Registration Dates

• First Submitted: March 14, 2024
• First Submitted That Met QC Criteria: March 29, 2024
• First Posted (Actual): April 5, 2024

Study Record Updates

• Last Update Posted (Actual): April 22, 2025
• Last Update Submitted That Met QC Criteria: April 16, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Other Study ID Numbers: ROM Study; PZ00P1_201972 (Other Grant/Funding Number: Swiss National Science Foundation)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data (data set and data dictionary)
• IPD Sharing Time Frame: Beginning 6 months after publication
• IPD Sharing Access Criteria: Researchers with a methodologically sound proposal
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No